Pharmaceutical agents or drugs exhibit desirable therapeutic properties because they contain distinct molecular arrangements called pharmacophores. Oftentimes, however, the pharmacophores or the presence of other chemical components within such compounds, provide a less than ideal overall profile relative to the final deployment of a given drug for a particular clinical indication. In some cases this situation can be improved by altering chemical features associated with a drug's distribution, metabolism or elimination (DME). This process, when successful, results in what is now referred to in the pharmaceutical community as a “soft drug” version of the original or parent drug compound: Soft Drugs. XX. Design, Synthesis and Evaluation of Ultra-ShortActing beta-Blockers, H.-S. Yang, W.-M. Wu and N. Bodor, Pharm. Res., 12, 329 (1995); and Synthesis and Enzymatic Hydrolysis of Esters, Constituting Simple Models of Soft Drugs, M. Graffner-Nordberg, K. Sjodin, A. Tunek and A. Hallberg, Chem. Pharm. Bull., 46, 591 (1998).
However, unless there is compelling preclinical data which suggests that the clinical application of a lead compound is going to become problematic, DME-related features are typically not rigorously evaluated in a chemical manner during the early process of new drug discovery and development. This situation has arisen, in part, because substantial clinical experience is often required to accurately define the sometimes subtle parameters of an undesirable DME feature relative to the beneficial aspects of a new drug while the latter is within the close purview of its actual clinical use in a specific pathophysiological setting. The problem of not knowing exactly what DME and toxicity-related properties may need to be addressed is additionally confounded by not having ready chemical blueprints for how to generally proceed even when a particular DME or toxicity issue becomes suspected.
The invention disclosed herein provides a ready method for altering DME and toxicity-related properties by deploying a specific chemical blueprint. The approach is useful to initially assess the DME parameters for an entire family of potential new drug candidate possibilities during the family's very early stages of structural refinement and preclinical study. When applied in this fashion, the inventive method expedites and improves the efficiency of the overall process of drug discovery and development.
Technologies which can enhance the efficiency of the drug discovery and development process have recently become of very high interest to the global pharmaceutical enterprise: Lead Generation and Optimization, Annual Meeting Strategic Research Institute, San Diego, Jun. 23, 1997; Emerging Technologies for Drug Discovery, International Biotechnology Event National Management Health Care Congress, Boston, May 19, 1997; and Pharmaceutical Education, Interim Meeting, American Association Colleges Pharmacy, Washington, D.C., Mar. 2, 1997.
Of equal significance but in more succinct and individually directed applications, the present invention is also useful for modifying the clinically established pharmaceutical agents where the specific therapeutic/side-effect details and benefits that might be associated with such DME alterations to a parent drug molecule are already recognized for a given indication. The current move to individualize drug treatment protocols within the evolving field of pharmacogenetics further underscores the very high interest and importance for having conveniently deployable technologies which can be generally applied toward fine-tuning and tailoring the overall pharmacological profile of a given drug for a given indication within a given individual: Recommendations of the NIGMS Working Group-Understanding Individual Variations in Drug Responses: From Phenotype to Genotype, R. M. Long and R. M. Weinshilboum, NIH Report 5 pages (Jun. 9–10, 1998).